[unreadable] [unreadable] While it is widely accepted that the risk of developing breast cancer is directly related to one's lifetime exposure to estrogen, the precise role of estrogen in the initiation and progression of breast cancer has yet to be determined. It has been hypothesized that initiation may result from induction of further DNA damage by estrogen metabolites in concert with preexisting lesions, while upregulation of mitogenic genes through the estrogen receptor (ER) may facilitate progression. While there is strong evidence that estrogen metabolites are tumorigenic in in vitro and animal models, the idea that estrogen metabolites can act as genotoxic carcinogens has existed for quite some time but remains controversial. Our previous studies have shown that the antioxidative stress enzymes, such as Quinone Reductase (QR) and Glutathione S-transferase Pi, are upregulated in response to the antiestrogen tamoxifen in breast epithelial cell lines. Our further dissection of transcriptional regulation of antioxidative enzymes has shown that this regulation involves Estrogen Receptor beta (ER initial study of the functional role for ER against estrogen-induced DNA damage. By identifying factors that inhibit estrogen-induced DNA damage we are in a good position to verify the role of estrogen metabolites in DNA damage and breast tumor initiation, and cancer prevention by antioxidative stress enzymes. Based on our findings we hypothesize that ER enzymes protects against the genotoxic effects of estrogens and thus prevents estrogen-mediated breast tumor initiation. To test our hypothesis we propose to determine: (1) What are the determinants of mammary tumorigenesis chemoprevention by antiestrogens? (2) Can QR inhibit the development of estrogen- induced early mammary cancer? Our proposed studies should provide important insights into the basis for cancer preventive effects of Selective Estrogen Receptor Modulators (SERMs). We will also develop new research models to test mammary cancer chemopreventive potential of SERMs. These mechanistic studies are critical for developing molecular-targeted approaches for chemoprevention, and the development of other models for testing promising new agents. [unreadable] [unreadable] [unreadable]